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Exciting interim MIST trial data elucidated the significant efficacy of aHSCT over DMTs. This Phase III study investigated highly active RRMS patients who experienced >2 relapses within the prior year despite receiving DMTs. The study met its primary endpoint in terms of treatment failure, with aHSCT patients 10 times less likely to fail treatment than those on DMTs during the mean three-year follow-up period. Encouragingly, positive results were also demonstrated across an array of secondary endpoints, most notably including a reversal of disability. Table 1 below summarizes the full dataset from the MIST trial, which was conducted across sites in the US, UK, Sweden, and Mexico.

Percentage treatment failure with mean follow up of three years (range 1–5 years) (%)

(Endpoint = Primary)

6 (3 of 52)

60 (30 of 50)

-54

Mean change in EDSS score from baseline to one year

-1.1

0.6

-1.7

(p<0.001)

Percentage NEDA at four years (%)

80

0-5

~75-80

(p<0.001)

Percentage EDSS failure-free survival at five years (%)

~90

~25

~65

(p=0.001)

Percentage change in T2 lesion volume (%)

-26.6

34.5

-61.1

Treatment failure was defined as EDSS >1.0 point sustained ≥6 months after ≥1 year of treatment, assessed by a blinded neurologist, while NEDA was defined as no relapses, no disability progression, no new or enlarging MRI lesions.

DMTs (number of patients) used in the control arm were: natalizumab (22), dimethyl fumarate (18), fingolimod (13), interferons (10), glatiramer acetate (8), and mitoxantrone (5). Other immune drugs used in the control arm include corticosteroids (39), cyclophosphamide (2), and rituximab (2).

The impressive efficacy of aHSCT in terms of expanded disability status scale (EDSS) reduction is unparalleled. Marketed DMTs have been limited to slowing disability progression, as opposed to demonstrating the 1.1 reduction in EDSS score that was remarkably evident with aHSCT. Moreover, at four years, there was a stark contrast in terms of no evidence of disease activity (NEDA) between the two arms, with 80% for aHSCT and 0–5% for the control arm. The complete absence of relapses, disability progression, and new or enlarging magnetic resonance imaging (MRI) lesions in aHSCT-treated patients drives home the sustained impact of this therapy as a potentially curative treatment.

It is promising that aHSCT’s efficacy in terms of EDSS was evident during the first year post-enrolment. Moreover, efficacy remained apparent for up to five years, with a low rate of treatment failure (6% = three patients) during follow-up. This indicates that treatment benefits are tangible relatively soon after aHSCT, and corroborates that positive benefits persist years later. Furthermore, incorporating numerous standard DMTs in the active comparator arm, including gold-standard Tecfidera (dimethyl fumarate; Biogen), only strengthens the data.

Safety and Tolerability of aHSCT

Thus far, aHSCT has appeared to be safe, with no deaths, no grade IV toxicity, and no early or late opportunistic infections such as fatal progressive multifocal leukoencephalopathy (PML), which is associated with some approved MS therapies like Tysabri. While there was one case of bacteremia during the vulnerable stage of neutropenia with aHSCT, there was no sepsis or hypotension.

Stem cell therapy is an intensive procedure that is typically used to treat cancers including leukemias and lymphomas. aHSCT aims to reset the immune system in MS patients (see Figure 1). The critical component of non-myeloablative aHSCT for MS is chemotherapy to partially eliminate the immune system, thus destroying auto-reactive cells. Following ablation, patients’ own harvested stem cells are reintroduced. These stem cells then differentiate into new, antigen-naïve immune cells without memory of MS. For a period, the patients are in an aplastic phase with little immune protection; hence, it is vital that they receive antimicrobial prophylaxis. Recovery times can take up to a year or sometimes longer [3].

Disease Background

MS is a chronic autoimmune and neurodegenerative disease that is estimated to affect at least 2.3 million people globally [4]. Inflammatory demyelination involving B and T cells within the central nervous system is a hallmark of this disease. In turn, demyelination leads to scar tissue formation, called sclerosis, along the covering of nerve cells. This process results in neurological symptoms associated with MS. MS is clinically heterogeneous – depending upon the site of the lesions associated with demyelination in the CNS. Primary symptoms of MS include cognitive dysfunction, muscle spasms, pain, fatigue, weakness, visual problems, numbness, bladder dysfunction, and difficulty walking [5].

The most common disease course is RRMS, which 85% of MS patients initially present with [6]. RRMS is characterized by intermittent attacks that are linked to residual disabilities. The vast majority of approved DMTs are indicated for the treatment of RRMS. Currently available DMTs are immunomodulators, anti-inflammatory, and immunomodulatory drugs. aHSCT is appropriate for a subpopulation of aggressive inflammatory RRMS that is typically characterized by frequent relapses, high MRI activity, and rapid disability accumulation [7].

Market Analysis

Since aHSCT is only suitable for a specific population of MS patients with severe RRMS that is treatment-refractory, it will pose a threat to DMTs reserved for highly active RRMS. aHSCT is an intensive treatment that will be consigned to a later line of therapy, for patients with few effective treatment options. Thus, it is unlikely to compete with DMTs prescribed for the wider RRMS population. Figure 2 below highlights Datamonitor Healthcare’s forecast sales for DMTs targeting highly active RRMS that are now at risk from serious competition [8]. Anticipated combined sales across the across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) for Gilenya, Lemtrada, Mavenclad, and Tysabri amount to $4.8bn in 2018 (see Table 2).

aHSCT is completely unique compared to available DMTs and is poised to fulfill critical unmet need for patients. A survey of 231 neurologists across the US, Japan, and five major EU markets, performed by Datamonitor Healthcare in May 2016, emphasized that the most pressing need in the MS market was for curative treatments [5]. aHSCT has the outstanding potential to offer a one-off treatment to patients, which could replace expensive lifelong therapy and therefore have substantial cost-saving implications. The cost of a year’s treatment may fall in line with marketed brands [9]. No pharmaceutical companies were involved in the MIST trial, with university centers likely to carry out this novel treatment as it becomes more widespread [1].

Barriers to Uptake

Existing cost infrastructures may not be amenable to aHSCT and patients may face difficulty accessing treatment. Additionally, there may be hesitance towards utilizing such an aggressive treatment in chronic MS patients as it is usually reserved for acute cancer patients who would die without treatment. aHSCT requires patients to tolerate a potent chemotherapy regimen that ablates the immune system. Consequently, patients must endure the aplastic phase during which they are extremely vulnerable to lethal opportunistic infections, therefore stringent monitoring and prophylactics are vital. aHSCT can be a demanding treatment for patients, necessitating a considerable recovery period.

It is also important to note that MIST was a relatively small trial with long-term data beyond five years yet to be released. Scrip Intelligence reported that patients treated in the MIST trial will be followed up until 2021 [10]. Longer-term follow up data will be key to consolidating aHSCT’s applicability for the MS treatment paradigm, as it is necessary to confirm that the therapy is indeed an efficacious one-off treatment and to establish its long-term safety and tolerability profiles. In addition, it would be interesting to ascertain how aHSCT compares clinically with new rising star Ocrevus (ocrelizumab; Roche), which is set to boast blockbuster sales, as Ocrevus was not yet available at the time of the trial.

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